Germline ESR2 mutation predisposes to medullary thyroid carcinoma and causes up-regulation of RET expression

Smith, Joel; Read, Martin; Hoffman, Jon; Brown, Rachel E.; Bradshaw, Beth; Campbell, Christopher; Cole, Trevor; Navas, Johanna Dieguez; Eatock, Fiona; Gundara, Justin S.; Lian, Eric; McMullan, Dom; Morgan, Neil V.; Mulligan, Lois M.; Morrison, Patrick J.; Robledo, Mercedes; Simpson, Michael A.; Smith, Vicki; Stewart, Shona; Trembath, Richard C.; Sidhu, Stan; Togneri, Fiona S.; Wake, N.; Wallis, Yvonne; Watkinson, John; Maher, Eamonn R.; McCabe, Christopher; Woodward, Emma R.

doi:10.1093/hmg/ddw057

Cited by 29 publications

(17 citation statements)

References 45 publications

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“…39 However, exome sequencing on a patient with MTC and no identifiable RET mutation has identified a germline frameshift c.948delT mutation in the ESR2 gene. 40 This mutation was also present in 3 family members with C-cell hyperplasia, and immunohistochemical studies confirmed its effect being the loss of ERβ and overexpression of RET. This finding of indirect up-regulation of RET expression leading to MTC provides an interesting insight into alternate pathways for developing MTC, although it has yet to be replicated by other researchers, and its role in sMTC is as yet unknown.…”

Section: Other Genetic Pathwaysmentioning

confidence: 80%

The role of molecular genetics in the clinical management of sporadic medullary thyroid carcinoma: A systematic review

Fussey

Vaidya

Kim

et al. 2019

Clinical Endocrinology

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Medullary thyroid carcinoma (MTC) is a malignant tumour of the neural crest-derived parafollicular C cells. Due to the recent increase in incidence of papillary thyroid carcinoma, MTC now comprises only 1%-2% of all thyroid cancers, 1 but accounts for a significant proportion of thyroid cancer morbidity and mortality. The rate of regional and distant metastasis at presentation is up to 35% and 13%, respectively, 2 and there has been no trend towards earlier stage at diagnosis or improved overall survival in recent decades. 3 Abstract Background: The significant variation in the clinical behaviour of sporadic medullary thyroid carcinoma (sMTC) causes uncertainty when planning the management of these patients. Several tumour genetic and epigenetic markers have been described, but their clinical usefulness remains unclear. The aim of this review was to evaluate the evidence for the use of molecular genetic and epigenetic profiles in the risk stratification and management of sMTC.Methods: MEDLINE and Embase databases were searched using the MeSH terms "medullary carcinoma", "epigenetics", "molecular genetics", "microRNAs"; and free text terms "medullary carcinoma", "sporadic medullary thyroid cancer", "sMTC", "RET", "RAS" and "miR". Articles containing less than ten subjects, not focussing on sMTC, or not reporting clinical outcomes were excluded. Risk of bias was assessed using a modified version of the Newcastle-Ottawa Scale. Results:Twenty-three studies met the inclusion criteria, and key findings were summarized in themes according to the genetic and epigenetic markers studied. There is good evidence that somatic RET mutations predict higher rates of lymph node metastasis and persistent disease, and worse survival. There are also several good quality studies demonstrating associations between certain epigenetic markers such as tumour miR-183 and miR-375 expression and higher rates of lymph node and distant metastasis, and worse survival. Conclusions:There is a growing body of evidence that tumour genetic and epigenetic profiles can be used to risk stratify patients with sMTC. Further research should focus on the clinical applicability of these findings by investigating the possibility of tailoring management to an individual's tumour mutation profile.

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Section: Other Genetic Pathwaysmentioning

confidence: 80%

The role of molecular genetics in the clinical management of sporadic medullary thyroid carcinoma: A systematic review

Fussey

Vaidya

Kim

et al. 2019

Clinical Endocrinology

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“…It should also be stressed that there are no previous reports of germline MET mutations in hereditary MTC. However, RET‐ negative hereditary MTCs are very rare and the only possible driver of such tumors identified thus far is a germline ESR2 mutation, which has also been documented in only one MTC kindred (Smith et al., ). Our failure to find MET alterations in other additional patients whose familial or sporadic MTCs had no known genetic drivers suggests that MET p.Arg417Gln is likely to be a private variant restricted to the kindred we analyzed.…”

mentioning

confidence: 99%

“…The authors also found MET variants involving the Sema domain in the exomes of three sporadic pheochromocytomas (Toledo et al., ). Of note, there are currently no reports implicating germline ESR2 mutations in pheochromocytomas or any other tumors of neural crest origin (Smith et al., ).…”

mentioning

confidence: 99%

Whole exome sequencing identifies a germline MET mutation in two siblings with hereditary wild-type RET medullary thyroid cancer

et al. 2017

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Whole exome sequencing (WES) was used to investigate two Italian siblings with wild-type RET genotype, who developed medullary thyroid cancers (MTCs) and, later, primary prostate and breast cancers, respectively. The proband's MTC harbored a p.Met918Thr RET mutation; his sister's MTC was RET/RAS wild-type. Both siblings had a germline mutation (p.Arg417Gln) in the extracellular Sema domain of the proto-oncogene MET. Experiments involving ectopic expression of MET p.Arg417Gln in MET-negative T47D breast cancer cells documented the mutant receptor's functionality and its ability to enhance cell migration and invasion. Our findings highlight a possible link between MET germline mutations and MTCs and suggest that MET p. Arg417Gln may promote an invasive malignant phenotype. The possibility that MTC can be driven/co-driven by a MET mutation has potential management implications, since the tyrosine-kinase inhibitor cabozantinib-approved for treating advanced MTCs-is a specific MET inhibitor.

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“…[148] Exome sequencing of MTCs associated with MEN2A also identified the expected RET mutations, but also suggested that low frequency mutations such as those found in EIF4G1 may also play a role in MEN2Aassociated tumorigenesis by indirectly altering the RET pathway. [158] A similar study was undertaken by Smith et al [159] in MTCs lacking an identifiable RET mutation. Interestingly, this group found a recurrent mutation in the ESR2 gene which encodes the estrogen receptor beta (ER).…”

Section: Nets -Thyroidmentioning

confidence: 87%

“…The authors propose that this may be a novel mechanism by which the RET gene is regulated in RET mutation-negative familial MTC. [159] Heilmann et al [164] performed genomic profiling of MTC cases during the course of clinical care and in addition to the expected RET mutations, also identified amplifications of CCND1, FGF3, FGF19 and CDKN2A. The authors propose that these may be cooperating driver mutations impacting chemoresistance and disease outcomes.…”

Section: Nets -Thyroidmentioning

confidence: 99%

Neuroendocrine tumors: current therapies, notch signaling, and cancer stem cells

Crabtree¹,

Miele²

2016

JCMT

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Neuroendocrine tumors (NETs) encompass a broad spectrum of malignancies all derived from neuroendocrine cell lineage, affecting many different organs including the gastrointestinal (GI) tract, the endocrine pancreas, the thyroid, the skin and the respiratory tract. These tumors as a group are very heterogeneous, with varying characteristics attributed to each tissue of origin and tumor subtype. The pathogenesis of the different subtypes of NETs is not fully understood, but recent studies suggest the Notch signaling pathway may be dysregulated in these tumors either by under or overexpression of Notch receptors and/or ligands, or by disruption of pathway functionality through other means. Notch receptors can function as tumor suppressors in some cellular contexts and oncogenes in others which may, in part, account for the wide range of phenotypes present in NETs. Cancer stem cells are present in these tumors and may be responsible for the high rate of chemotherapy resistance, recurrence and metastasis. The heterogeneity of NETs suggests that to fully understand the role of Notch signaling and the therapeutic implications thereof, a comprehensive and systematic analysis of Notch expression and function across all NET subtypes is required. Here we outline the current knowledge base with respect to current therapies and Notch signaling in neuroendocrine tumors of the lung, skin, thyroid, GI tract and endocrine pancreas.

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Germline ESR2 mutation predisposes to medullary thyroid carcinoma and causes up-regulation of RET expression

Cited by 29 publications

References 45 publications

The role of molecular genetics in the clinical management of sporadic medullary thyroid carcinoma: A systematic review

The role of molecular genetics in the clinical management of sporadic medullary thyroid carcinoma: A systematic review

Whole exome sequencing identifies a germline MET mutation in two siblings with hereditary wild-type RET medullary thyroid cancer

Neuroendocrine tumors: current therapies, notch signaling, and cancer stem cells

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